Cell adhesion and migration contribute to normal processes such as differentiation, embryonic development, and wound healing as well as to the progression of diseases and pathological conditions that can result from either acute or chronic exposure to environmental toxicants, such as cancer and inflammatory responses. Key mechanistic steps in these processes involve the interactions of extracellular glycoproteins--such as fibronectin, laminin, and collagens--with specific adhesive receptors, the best characterized of which are the integrins, a family of heterodimeric complexes consisting of an alpha subunit and a beta subunit. Integrins are highly regulated receptors that can exist in either an active or inactive state. The overall goal of our research is to characterize the molecular mechanisms of integrin-mediated adhesion processes, integrin activation, and the resulting downstream processes induced by adhesive proteins such as fibronectin important for the control of proliferation, adhesion, migration, and invasion of cells with a particular emphasis on human tumor cells. Our current work focuses on biochemical and biological consequences of integrin activation, ligand occupancy, and the signal transduction pathways that play roles in the modulation of cell-cell and cell-substrate adhesion. Integrin activators such as peptide ligands, divalent cations (especially manganese ion), and certain monoclonal antibodies, were initially identified by their ability to increase cell-substrate adhesion. We have found that integrin activation by a specific antibody, 12G10, can also modulate other processes such as cell-cell adhesion and intracellular signaling pathways. Integrin-mediated cell-cell adhesion appears to require signaling processes that can be very complex and involve multiple systems including cytoskeletal proteins and PKA-mediated cAMP second messenger signaling pathways that lead to biochemical changes such as protein phosphorylation. The precise roles of these signaling processes in the mechanism of integrin function are currently being characterized.